Irritable bowel syndrome (IBS), a common gastrointestinal disorder characterized by abdominal pain and a change in bowel habits, will affect up to 20% of the general population. Epidemiological studies have established that females are 2-5x more likely to suffer from IBS in comparison to males. A defining characteristic of IBS is severe gastrointestinal pain. Surprisingly, while an extensive body of research has been conducted examining the neural mechanisms underlying visceral pain, these studies have been conducted exclusively in males. Thus, it is not known how visceroceptive information is processed within the CNS of females. Similarly, the impact of gonadal steroids on visceral pain is also not known. Behavioral studies in Aim 1 will characterize the sex differences and influence of gonadal steroids on visceral pain. Our preliminary data indicate that there are profound sex differences in the visceral motor reflex, an indicator of visceral pain following noxious colorectal distention. Our data further show that the sexually dimorphic response to noxious visceral stimulation is estrogen dependent. Anatomical studies proposed in Aim 2 will test the hypothesis that sex differences in the organization and activation of the spinoparabrachial circuit provide the anatomical substrate for the dimorphic response to noxious visceral stimulation. Studies using acute somatic stimuli have reported that morphine produces a significantly greater degree of analgesia in males versus females, and our preliminary studies indicate that morphine alleviation of visceral pain is also sexually dimorphic. Studies proposed in Aim 3 will test the hypothesis that morphine produces a significantly greater degree of analgesia in males in comparison to females in a model of visceral pain. Immunocytochemical and molecular studies proposed in Aim 4 will test the hypothesis that opioid receptor expression within the lumbosacral spinal cord is sexually dimorphic. The influence of gonadal steroids on opioid receptor expression will also be examined. Together, these studies will begin to elucidate the neural mechanisms underlying sex differences in visceral pain.